Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) refers to a heterogenous group of allelic disorders deriving from germline mutations in the phosphatase and tensin homolog (PTEN) gene. The PTEN gene, located on chromosome 10q23, functions as an inhibitor of the PI3K/AKT/mTOR pathway, which controls angiogenesis and cell proliferation. As a known tumor suppressor gene, pathologic variants lead to loss of phosphatase function, which allows for upregulation of the PI3K/AKT/mTOR pathway leading to decreased apoptosis and increased cell growth.1
Most commonly recognized PHTS disorders include Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome and autism spectrum disorders associated with macrocephaly.2 These syndromes were first described as separate disorders based on constellations of common phenotypic features including macrocephaly, vascular malformations, polyps of the gastrointestinal tract, hamartomas, and their known increased risk for malignancy (breast, thyroid, endometrial, colorectal, and renal cancers as well as malignant melanoma). These diverse syndromes would later be identified as sharing a common germline PTEN etiology that is inherited in an autosomal dominant manner and occurs with a prevalence of 1/200 000.3–6 There remains a broad variability of clinical presentation with no clear genotype to phenotype correlation.
Evidence-based diagnostic guidelines for CS were published in 2013 and adopted by the US National Comprehensive Cancer Network (NCCN).7 The NCCN established indications for PTEN testing based on the clinical features present in a patient and outlined recommendations for prophylactic surveillance for individuals identified to have a germline PTEN mutation.8 The diagnosis remains challenging in pediatrics as age-related penetrance makes it difficult to satisfy diagnostic criteria. Many consider macrocephaly to be a universal finding (80%–100% of patients)9; however, our patient cohort outlined in this report indicates a broader spectrum than previously recognized.
Vascular anomalies have been known to occur in patients with PTEN mutations. Both vascular tumors (ie, dynamic division of benign or malignant vascular cells) and vascular malformations (ie, errors of vascular embryogenesis) have been observed in a single review by Tan et al.10 A cohort of patients was described in this study with recurrent diffuse infiltrative intramuscular tumors referred to as PTEN hamartomas of soft tissue (PHOST). PHOST lesions were pathologically defined in a subsequent publication by Kurek et al11 as containing: (1) variable admixture of mature adipocytic and dense and/or myxoid fibrous tissue; (2) clusters of venous channels, thick-walled arteries, occasional arteriovenous communications; (3) lymphoid follicles; (4) foci of bone; and (5) hypertrophic nerves.10,11 PHOST lesions may contain slow-flow and/or fast-flow vascular anomalies.12 The International Society for the Study of Vascular Anomalies has had difficulty categorizing PHOST as either a vascular tumor or malformation.
In most published guidelines to date (eg, NCCN), patients with infiltrative soft-tissue lesions are guided to test for PTEN mutations given only the presence of additional physical syndromic features consistent with criteria for PHTS. One published case report describes an intramuscular PHOST lesion as the initial presenting symptom that led to the diagnosis of PHTS.13 Additionally, a larger chart review noted 2 of 26 patients that were diagnosed with PTHS after identification of a PHOST.10 We present 4 cases of children who presented with isolated infiltrative soft-tissue lesions, which prompted tissue-based commercial sequencing revealing the diagnosis of germline PTEN mutations. None of the subjects had baseline documentation of systemic abnormalities including macrocephaly, gastrointestinal polyps, or developmental delay. All patients were previously misdiagnosed, inaccurately classified as either a hemangioma, arteriovenous malformation, or venous malformation. Targeted next-generation sequencing (NGS) was sent on tissue in consideration of somatic overgrowth syndromes to better define the lesions and to guide therapy in these aggressive and functionally devastating lesions. Testing revealed pathogenic germline PTEN mutations in all cases. Accurate diagnosis immediately initiated lifelong screening protocols to monitor for the development of malignancy and testing of parents to assess familial risk and predisposition for cancer.
An 11-year-old Caucasian male presented with a large, painful left intramuscular thigh lesion. No additional medical or family history was reported. Medical history included a surgical biopsy of the thigh lesion.
Initial examination demonstrated an enlarged left thigh compared to the right (Figure 1A). The patient reported daily focal pain impacting activity. Ultrasound and magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) demonstrated a large mass in the adductor muscle with large venous channels and a possible component of arteriovenous malformation (AVM) (Figure 1B–D). Tissue histology demonstrated a mixed soft-tissue lesion composed of skeletal muscle, adipose tissue, and variable sized vessels (Figure 1G and H).
Treatment consisted of a series of 4 interventional procedures involving diagnostic angiography and therapeutic embolization. Initial angiograms demonstrated a left thigh arteriovenous malformation supplied by both the superficial femoral artery and profunda femoris (Figure 1E). This was then embolized in a stepwise fashion with coils and the liquid embolic agent Onyx (Figure 1F). Plans were made for repeat serial embolizations. As with most AVMs, subsequent angiograms demonstrated parasitized arterial supply from neighboring vessels including branches of the circumflex femoral artery. This was again treated with coils and Onyx embolization 2 more times. Angiograms from the fourth intervention noted further extensive arterial recruitment from the left superficial femoral artery and profunda femoris to the previously partially treated lesion. A combination of Onyx, Amplatzer Vascular Plug, and coil embolization was used to treat the remaining visible lesion. Postprocedural imaging demonstrated an overall 60% reduction in size of the lesion.
Tissue from the surgical biopsy of the vascular anomaly was sent for clinical genetic evaluation via a somatic overgrowth panel (https://gps.wustl.edu/patient-care/rare-disease/). The panel returned positive for a variant in the PTEN gene and Sanger sequencing confirmed a variant of germline origin. The variant was reported as a novel in-frame insertion-deletion variant p.N276_T277delinsP. The variant impacts amino acids located at the junction of the phosphatase and C2 domains of PTEN; the 3bp deletion removes asparagine 276 and substitutes threonine 277 with a proline.14 Patients have been reported in the literature with additional variants affecting these amino acids and diagnoses including breast cancer and PHTS.15–17
After diagnosing a germline PTEN mutation, comprehensive evaluation for a systemic syndrome failed to demonstrate macrocephaly, any evidence of developmental or motor delay, or any skin findings. Screening ultrasound of his thyroid was negative. His mother did report a history of uterine cancer in her 30s, and there was family history of male breast cancer. His mother was negative for the PTEN mutation, but her testing revealed a diagnosis of Lynch syndrome.
A 9-year-old Caucasian female presented for evaluation of a right medial calf mass. She had a negative past medical, surgical, and family history.
Physical examination noted a protuberant, slightly firm, nonmobile mass with no overlying skin discoloration (Figure 2A). Ultrasound demonstrated heterogenous tissue along the right lower leg with minimal vascularity and intralesional thrombosis of uncertain etiology. MRI demonstrated a vascular lesion within the subcutaneous soft tissues of the medial aspect of the leg (Figure 2B). MRA noted arterial feeding vessels and overall arterial enhancement of the lesion (Figure 2C). Angiography showed small arterial vessels originating from the peroneal artery supplying the lesion (Figure 2D). Arterial contrast blush was present in the protuberant region along the right medial calf with early venous drainage from microvascular shunting.
Incisional biopsy was performed to establish a diagnosis. Tissue histology demonstrated a predominant venulocapillary component within fibroadipose tissue, with focal arteries identified (Figure 2E and F). The pathologic differential included fibroadipose vascular anomaly (FAVA) and AVM.
Tissue from the surgical biopsy of the vascular anomaly was sent for a genetic evaluation via somatic overgrowth panel. The panel returned positive for 2 PTEN gene mutations. The first variant was a pathogenic nonsense mutation of p.E242, which is predicted to result in a truncated mRNA product subject to nonsense mediated decay and leading to loss-of-function allele. This variant is absent in the population database (https://gnomad.broadinstitute.org).18 The second variant was a pathogenic frameshift p.R130Efs*4 leading to a C nucleotide deletion resulting in a TAA stop codon 4 amino acids after the R130 residue. This is also theorized to result in a loss-of-function allele. This specific variant has been identified as a somatic variant in malignancies, but not previously identified as a pathogenic germline variant.19–21 Genomic distance precludes determination of cis/trans allele. A trans allele relationship would predict biallelic loss of function. Sanger sequencing confirmed the variant p.E242 is present and is likely germline in origin. Variant p.R130Efs*4 was not noted on Sanger sequencing.
After diagnosing a germline PTEN mutation, comprehensive evaluation for a systemic syndrome demonstrated mild macrocephaly, but no developmental or motor delay, or any skin findings. Screening ultrasound of her thyroid was negative. No additional family history of malignancy was reported. Parents were negative for a germline mutation in PTEN.
A 7-year-old Caucasian female presented with history of painful left knee “hemangioma.” Medical and family history are unremarkable. Past surgical history is significant for 4 previous surgical resections at outside institutions, each followed by recurrence, associated pain, and limitations in knee joint mobility with limb length discrepancy of 1.7 cm.
Physical examination demonstrated a warm soft tissue vascular anomaly of the left knee with limited joint extension, marked baseline pain, and a 1.7-cm limb length discrepancy (Figure 3A). MRI demonstrated partially enhancing heterogenous tissue with postsurgical changes along the anteromedial aspect of the knee (Figure 3B).
Early therapeutic intervention consisted of continued use of a brace for support and mobility and 9 rounds of angiography with embolization and percutaneous sclerotherapy to decrease size of the lesion using Onyx and ethanol (Figure 3C and D). Procedures successfully decreased daily pain and allowed her to wean use of knee brace.
Tissue from a prior surgical resection was sent for genetic evaluation via somatic overgrowth panel (Figure 3E and F). The result was positive for a PTEN gene variant. The specific variant is described as a likely pathogenic frameshift mutation of p.S113Rfs which results in a loss-of-function allele. This variant has been reported once before in the setting of a glioblastoma, but has not been reported as a germline variant.19,20
After diagnosing the germline PTEN mutation, comprehensive evaluation for a systemic syndrome failed to demonstrate macrocephaly, or any evidence of developmental or motor delay. Evaluation did identify a papilloma on her lip, several flesh-colored papules on her fingers, and a small capillary stain on her lower back. Screening ultrasound positively identified thyroid nodules. Fine needle aspiration demonstrated benign follicular nodules.
A 13-year-old Hispanic female presented with acute swelling from a left forearm mass causing pain and impacting elbow and wrist joint mobility. Patient reported intermittent neuropathy in her fingers. She had a prior direct angiogram of the forearm lesion which noted multiple small arterial feeder vessels, venous lakes, and serpiginous channels, all concerning for an AVM, and she completed one round of ethanol embolization. No other medical, surgical, or pertinent family history was reported.
Examination demonstrated a tense, protuberant subcutaneous left forearm mass with the overlying skin demonstrating a faint blue discoloration (Figure 4A). MRI prior to intervention noted a heterogeneous mass over the left distal radius extending primarily over the volar surface, extending deep to the interosseous space between the distal radius and ulna (Figure 4B). MRA at the time did not reveal an arterial component and this was thought to represent a venous malformation. Percutaneous sclerotherapy was performed with sodium tetradecyl sulfate 3% with some transient relief (Figure 4C).
She was reevaluated at 17 years of age due to continued complaints of swelling, pain, and decreased hand function. MRI demonstrated a complex infiltrative vascular malformation with substantial adipose tissue component throughout the mid to distal forearm, with small foci of late arterial enhancement arising from the posterior interosseous artery (Figure 4D). Open tissue biopsy was performed with tissue histology described as fibroadipose tissue with variably sized and variably dilated vascular channels; FAVA diagnosis was favored (Figure 4E and F).
Acute therapeutic intervention was with sirolimus (Rapamune), an mTOR inhibitor. Starting dose was 0.8 mg/m2 per dose given twice a day and titrated to a trough serum level of 10–15 ng/ml. She was concurrently placed on Pneumocystis jiroveci pneumonia prophylaxis with Bactrim. She demonstrated marked improvement in pain, softening of the lesion, and decrease in neuropathy during a 1-year course of therapy; no appreciable decrease in lesion size was noted.
Tissue from biopsy was sent for somatic overgrowth panel testing. The panel returned positive for a variant in the PTEN gene. The specific mutation was described by the testing laboratory as a novel mutation, a likely pathologic missense variant of p.V343E. The location is in a highly conserved base position within lipid binding C2 domain. In vitro studies of this region have demonstrated that this mutation leads to a reduction in PTEN phosphatase activity.22,23 The variant may additionally cause decreased binding to and phosphorylation by PICT-1, a PTEN stabilizing protein.22
After diagnosing a germline PTEN mutation, comprehensive evaluation for a systemic syndrome positively demonstrated mild macrocephaly and mild learning difficulties during primary education. Neither finding had been identified previously in her primary pediatric records. Screening ultrasound of her thyroid demonstrated a 6-cm nodule in the left thyroid lobe and abnormal lymph nodes in zones 2 and 6. Total thyroidectomy was performed via neck dissection due to size of the mass and concerns for malignancy. Thyroid pathology was consistent with follicular adenoma and lymphocytic thyroiditis. An endometrial biopsy was obtained due to history of menorrhagia, which demonstrated atypical polypoid adenomyoma with features worrisome for atypical hyperplasia. Endometrial curettage noted atypical hyperplasia with squamous morular metaplasia. A levonorgestrel-releasing intrauterine device (LNG-IUD) was placed to potentially preserve future fertility.
This case series reports 4 children with germline PHTS who initially presented with only an isolated PHOST lesion of the extremity (Table 1). Baseline clinical history and physical examination lacked evidence for a specific syndrome. These patients did not meet NCCN screening guidelines to send sequencing evaluation for germline PHTS.
Table 1. -
Patient Demographics at Diagnosis
||Additional PTHS Features
||L adductor (intramuscular lesion)
||R calf (soft-tissue lesion)
||L knee (intra-articular lesion)
||L forearm (intramuscular lesion)
||Mild learning difficulties, and mild macrocephaly†
PHOST, PTEN hamartomas of soft tissue; PTEN, phosphatase and tensin homolog; PTHS, PTEN hamartoma tumor syndrome.
*p.R130 mutation not detected in the germline.
†PTHS features were diagnosed in retrospect after identification of PTEN mutation.
Radiographically, their lesions were broadly identified as complex soft tissue vascular anomalies with both slow-flow and fast-flow components. PHOST lesions specifically demonstrate serpiginous vessels with disruptive, fibrofatty infiltration of muscle, fascia, and can involve bone. Histologically, the differentials documented on reports of their lesions were thought to favor FAVA or AVM. Our case series demonstrates the importance of a genetic diagnosis for vascular anomalies; all 4 cases had pathogenic PTEN germline mutations. Accurate genetic diagnosis defined the vascular anomaly as part of a germline PHTS syndrome with lifelong potential oncologic implications for the patient as well as consideration for familial testing.
A diagnosis of PHTS is associated with a lifelong risk of malignancy and appropriate surveillance is required for both the patient and affected family members that share the PTEN mutation.24 Women carry an 85% lifetime risk of breast cancer and a 28% risk of endometrial cancer. All affected patients carry a 35% lifetime risk of thyroid cancer, 9% risk of colon cancer, and 6% risk of melanoma.1,2,7,8
Historically, the diagnosis of PTHS has been based on national clinical diagnostic criteria, which guide surveillance screening and familial testing.7 It is difficult to apply this guideline to all children because it relies on macrocephaly as a major criterion for diagnosis; a study published in 2007 noted this as a universal finding.10 Two of our subjects lacked macrocephaly and 2 had minimal macrocephaly diagnosed only in subsequent screening evaluations. Additionally, the diagnostic criteria developed by Pilarski et al7 include macrocephaly as a major diagnostic criterion. Cutaneous finding such as trichilemmomas and oral papillomas often do not appear until the second decade or adulthood, so they are not reliable physical findings in pediatric patients.7 Furthermore, trichilemmomas are clinically indistinguishable from other benign skin lesions and visual examination cannot be relied upon for diagnosis.7
Per revised diagnostic criteria by Pilarski et al,7 all 4 cases would not have met criteria for germline PTEN testing based on initial presentation to our clinic. In retrospect, only cases 2 and 4 demonstrated mild macrocephaly, with case 4 also describing mild learning difficulties in school. Our patient in case 4 would not have met diagnostic criteria to screen for PTHS at presentation given her mild learning disability (minor criteria defined as an IQ < 75) and macrocephaly had yet to be recognized.7 With the additional findings of thyroid nodules and atypical uterine hyperplasia, case 4’s phenotype may be consistent with a variant of PTEN-related Cowden syndrome. Our series supports further investigation into the possibility of PTEN in patients with complex soft-tissue vascular anomalies containing both slow-flow and fast-flow components.
Complicating the ability to diagnose an isolated PHOST of the extremity are the overlapping clinical features of several vascular lesions. Evaluation of a soft-tissue vascular anomaly is currently made with the assistance of radiologic and pathologic evaluation. Lesions are heterogenous in nature, leading to biopsy samples that are not entirely representative of the mass. Genetic assessment has become increasingly critical in this field. Lesions causing varying degrees of diagnostic uncertainty in these case studies include FAVA, AVM, and PHOST, which are defined in Table 2.25–28
Table 2. -
Clinical, Radiographic, and Histologic Descriptions of FAVA, AVM, and PHOST
||FAVA is a vascular anomaly that demonstrates pain out of proportion to a standard venous malformation, joint contracture, and fibrofatty infiltration of the soft tissue and muscle
||Ultrasonography demonstrates heterogenous echogenic changes, possible clots and phleboliths, but no high-flow component.25,26 MRI demonstrates a soft tissue lesion with high signal intensity on the T1-weighted images and a high signal intensity on T2 images.26 Venography may note anomalous dilated veins within the lesion; angiography does not note a high-flow component25
||Histopathology demonstrates dense fibrous tissue, excessive fat, venous malformation, and lymphoplasmacytic aggregates in the skeletal muscle. Small, clustered, irregularly muscularized venous channels will be noted25
||An AVM is a high-flow vascular anomaly that inappropriately connects arteries to veins without the normal small vessel arterioles or capillaries27
||Ultrasonography demonstrates the fast-flow and MRI generally demonstrates groups of prominent vascular channels with dilated feeding and draining vessels; a distinct mass may not be noted.27 Signal void may be noted and there may be increased fat deposition in the surrounding tissues and overgrowth of the affected tissues. MRA may show enhancement of enlarged vessels within the lesion
||Histopathology demonstrates malformed arteries and veins with nonuniform myxoid degeneration in vessel walls28
||PHOST lesions often present in adolescence as a painful soft-tissue lesion of an extremity25
||A single report of ultrasound findings describes PHOST as an ill-defined, heterogenous, echogenic soft tissue mass, with moderate internal vascularity.13 MRI demonstrates variable sized lesions with infiltration of muscle, fascia, and subcutaneous tissue. Enlarged serpiginous vessels may be present.27 MRI and CT often demonstrate fatty infiltration within the masses
||Histologically, the mass is not encapsulated, and excessive adipose tissue is present along with thin-walled irregular vessels and arteries; thick-walled arteries with pinpoint lumina are also present.25,28 Arteriovenous communications may also be present
AVM, arteriovenous malformation; FAVA, fibroadipose vascular anomalies; MRI, magnetic resonance imaging; PHOST, PTEN hamartomas of soft tissue; PTEN, phosphatase and tensin homolog; PTHS, PTEN hamartoma tumor syndrome.
PHOST lesions can be confused with the clinical, radiographic, and pathological features of FAVA and complex venous malformations. Genetic evaluation of vascular anomalies has become common to aid in proper diagnosis. Targeted NGS panels are recommended to identify overgrowth syndromes. In consideration of genetic causes of vascular anomalies, one must consider germline versus somatic mutations. Somatic mutations occur postzygotically and are localized to the affected tissue. Consideration of a somatic overgrowth disorder requires a biopsy of affected tissue. In contrast, germline mutations originate from the sperm or the egg and occur throughout the body. These mutations are detected in DNA isolated from the blood, skin, hair, or nails and do not require biopsy of affected tissue. FAVAs are increasingly associated with somatic PIK3CA mutation. Extremity AVMs have been associated with somatic MAP2K1, KRAS, NRAS, and BRAF mutations and germline RASA1, EPHB4, and PTEN mutations.29–32PTEN is often included in somatic overgrowth panels, although typically represents a germline mutation. In our four cases, specifically affected tissue was sent for testing and yielded PTEN mutations in all cells (Table 3). Confirmatory testing was completed on DNA isolated from peripheral blood. All four confirmed germline PTEN mutations. The patient in case 2 had 2 identified mutations which is likely to reflect the 2-hit Knudson’ hypothesis in which a single mutation in one allele of a tumor-suppressor gene is not sufficient to initiate tumor growth and requires a second mutation in the trans allele to result in unregulated cell growth. Although high-level mosaicism could explain the lack of family history in our series of “de novo” variants, detection in the blood and in 100% of the affected cells in the patients suggest this is less likely. The NGS panel successfully categorized a second hit in case 2 as mosaic. It is of interest the cases all represent de novo germline mutations and more studies to understand de novo cases in individuals specifically presenting with PHOST lesions will be helpful. Patients were counseled on the variable expressivity within families.
Table 3. -
Genetic Characterization of PTEN
||Reduced ability to inhibit downstream AKT phosphorylation14
||Stop codon at E242 residue, subject to nonsense-mediated decay, leading to loss-of-function allele
||Truncated mRNA product subject to nonsense mediated decay, leading to loss-of-function allele
||1 prior report in glioblastoma
||5bp deletion predicted to result in protein truncation within the catalytic phospotase domain, leading to loss-of-function allele
||Reduction of PTEN phosphatase activity and decreased binding to and phosphorylation by PICT-1, a stabilizing PTEN-interacting protein
PTEN, phosphatase and tensin homolog.
*Variant p.R130Efs*4 was NOT present in the germline.
PHOST lesions can cause significant functional impacts on an extremity limiting joint mobility. Direct or indirect involvement of muscles and nerves results in pain that can be debilitating to quality of life. PHOST do not involute or resolve over time and, with a fast-flow component, tend to progress and recur. Appropriate consultation with a multidisciplinary vascular anomaly team familiar with PHOST is necessary before attempting therapeutic intervention. Surgical excision often requires complete removal of the involved tissue or muscle. Orthopedic surgeons can be engaged to determine functional impacts of resection. Orthopedic evaluation in cases 1 and 4 determined that surgical resection would likely result in unacceptable impairment of motor function. Case 3 presented after four previous surgical resection attempts; the PHOST had recurred after each procedure. Several interventional therapies have been trialed on PHOST lesions including staged embolization and percutaneous interstitial sclerosant injections. However, case reports of PHOST managed with endovascular treatments report little improvement.12 Sclerosing agents reported to be attempted in PHOST include dehydrated alcohol, bleomycin, 3% sodium tetradecyl sulfate; embolics include onyx, coils, and plugs.12 Case 1 demonstrated a decrease in lesion size and associated pain with multiple rounds of coil, onyx, and plug embolization. Case 3 also demonstrated control in size and improved mobility after multiple rounds of ethanol embolization; however, she developed skin ulcerations with the most recent embolization treatment.
Sirolimus (Rapamune) is an mTOR inhibitor that has been increasingly utilized off-label to improve functional impairment in vascular anomalies with upregulated PI3K/AKT/mTOR activity. Initial studies demonstrated efficacy to improve symptoms in lymphatic malformations and Kaposiform hemangioendothelioma. More recent trials have begun to demonstrate efficacy in complex vascular anomalies with overgrowth with some evidence of response for both FAVA and PHOST lesions.12,33–36 Sirolimus was demonstrated to be well tolerated in patients with Cowden syndrome and was associated with some level of improvement in symptoms, skin and GI lesions, cerebellar function, and decreased mTOR signaling.33 Sirolimus was trialed off-label in case 4 at a starting dose of 0.8 mg/m2/q12hr and titrated to a serum trough level of 10–15 ng/ml. The patient was placed on concomitant of sulfasoxazole-trimethoprim for Pneumocystis jiroveci pneumonia prophylaxis. Within three months of therapy she reported marked improvement in pain, decreased distal neuropathy, and softening of the lesion with no notable decrease in overall lesion size.
Historically, germline PTHS would not be considered in the differential diagnosis of isolated soft-tissue vascular anomalies of the extremity without additional physical examination findings to suggest a more systemic syndrome such as macrocephaly or developmental delay. Based upon our experience, we advocate consideration of PTHS and PTEN gene testing in cases of isolated soft tissue vascular anomaly of the extremity, particularly if a fast-flow component is detected. PTHS can present as an isolated PHOST lesion without systemic findings and establishing a genetic diagnosis is crucial to the patient’s future health. Furthermore, a multidisciplinary team of specialists experienced with the radiographic, pathologic, and genetic features of PTHS and PHOST lesions will more rapidly lead to an accurate diagnosis. Establishment of proper diagnosis will guide treatment options and allow for recommended screening for associated cancers. Prospective studies are necessary to understand the true prevalence of patients with PTHS and to better identify genotype to phenotype correlation.
We would like to thank Washington University School of Medicine, Genomics and Pathology Services, St. Louis, MO, for assisting with patient and family germline testing.
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